The formation of new blood vessels either from differentiating endothelial cells during embryonic development (vasculogenesis) or from pre-existing vessels during adult life (angiogenesis) is an essential feature of organ development, reproduction, and wound healing in higher organisms. Angiogenesis is also necessary for certain pathological processes including tumorigenesis and retinopathy. While several growth factors can stimulate angiogenesis vascular endothelial growth factor (VEGF) is a potent angiogenic factor that acts via the endothelial cell-specific receptor tyrosine kinases fms-like tyrosine kinase (Flt1) and fetal liver kinase (Flk1) (also designated KDR). These two VEGF receptors and a third orphan receptor, Flt4 constitute a subfamily of class III receptor tyrosine kinases that contain seven extracellular immunoglobulin-like domains and a split intracellular tyrosine kinase domain. These three receptors have 31-36% amino acid identity in their extracellular ligand-binding domains.
VEGF is a homodimeric, cysteine-rich protein that can occur in at least four forms due to alternative splicing of its mRNA. VEGF is a high-affinity ligand for Flt1 and Flk1. A closely related member of the VEGF family is placental growth factor (PlGF), which has 47% amino acid identity with VEGF. PlGF also occurs in two alternatively spliced forms which differ in the presence or absence of a basic heparin binding domain of 21 amino acids.
Various natural and synthetic mechanisms exist for modulating growth factor activity including those that regulate the availability of agents that interact with growth factors in situ and in vivo. Accordingly, additional compounds, compositions and methods for regulating growth factor-agent interactions are desirable.